Circulatory adjuvant shell elements for cardiac glycoside suppository cores



Feb. 25, 1964 J. H. SCHAEPPI 3,122,475

CIRCULATORY ADJUVANT SHELL ELEMENTS FOR CARDIAC GLYCOSIDE SUPPOSITORYCORES Filed Feb. 25

l2 SHE A Cl JNVENTOR. J'O/MMV flaw/6H SCH/45PM BY M M W ATTOIQ/VEYSUnited States Patent 3,122,475 CIRCULATORY ADJUVANT SIELL ELEMENTS FORCARDEAC GLYCDSWE SUPPGSITGRY CGRES Johann Heinrich Sehaeppi, Mitlodi,Switzerland, assignor to Dr. Schaeppi Alrtiengeseilschaft, Mitiodi,Switzerland, a corporation of Switzerland Filed Feb. 25, 1960, Ser. No.10,996 8 Claims. (Cl. 167-64) This invention relates to a suppositoryeffective in the treatment of heart disease, and more particularly to amultiple lay'er suppository containing sequentially acting medicamentseffective in treating heart decompensation.

The various cardiac glycosides have in recent years found increasedutility in therapeutic treatments designed to improve heart muscleactiw'ty and tone. However, it has been noted that While suchmedicaments possess beneficial positive inotropic effects, neverthelessthey do not simultaneously supply the heart with sufficient amounts ofblood. The effects of such deficiency are manifest; on one hand, thecardiac glycosides fail to fulfill their function of assisting the heartmuscles to maintain adequate circulation, while, on the other hand, useof these medicaments, particularly in cases involving elevatedtherapeutic dosages, may presage systaltic heart failure. In the lattersituation the blood supply may actually so lag behind the increasedactivity of the heart muscles, induced by the heart glycoside, that thephysiological residual blood may be pumped out of the heart and idlebeating of the chambers will result.

Clinical tests have indicated that the effect of the cardiac glycosidesmay be significantly improved after a preliminary administration of acirculatory adjuvant, such as camphor. In fact, it has been shown thatthe danger of systaltic heart stoppages, after administration ofstrophanthin and other cardiac glycosides, is greatly diminished by sucha preliminary treatment (Brodhage and Carrel, Arzneimittelforchung,1957, No. 7). Such effect is believed to result from the adjuvantsaction effecting increased flow of blood to the right atrium, therebyincreasing the heart discharge capacity. Thus, the cardiac glycoside,which is thereafter administered, functions to improve circulationwithout danger of systaltic failure.

Pharmacologically, the efiect resulting from the successiveadministration of a circulatory adjuvant and a cardiac glycoside attimed intervals has been designated the Interval Eifect by Carrel. Whenthe circulatory adjuvant is given sufficient time to be absorbed intothe circulatory system and the cardiac glycoside is immediatelythereafter absorbed, a truly synergistic therapeutic effect results.Such interval eifeot is different in kind from the mere pluraladministration of different doses of the same therapeutic agent anddepends upon the cooperative functions of the two specific medicamentsresulting from sequential administration of first the circulatoryadjuvant such as camphor and then at a specific time intervalthereafter, the cardiac glycoside.

Unfortunately, circulatory adjuvants such as camphor cannot beadministered intravenously but have rather heretofore been administeredby intramuscular injection. When camphor dosages are given in suchfashion, it has been found that between one and two hours are requiredfor absorption into the circulatory system. In order therefore toachieve the beneficial results accruing from the Interval Effect, thephysician must wait for one hour or more before administering thecardiac glycoside. Such delay has proven quite a burden upon both thepracticing physician and the patient, particularly in view ice of thefact that in many' cases daily injections of the therapeutic agents arenecessary.

It is accordingly an object of the present invention to provide meansfor administering a circulatory adjuvant and a cardiac glycoside atdesired intervals to effectuate treatment of heart decompensation.

A further object of the present invention is to provide for thespecifically timed sequential administration of a circulatory adjuvantand a cardiac glycoside without necessitating undue use of thephysicians time and without causing the patient undue pain ordiscomfort.

Other objects and advantages of the present invention will becomeapparent from the following detailed description of the invention andthe appended claims defining the scope thereof.

In accordance with my invention, a plural medicament containing layeredsuppository for the treatment of heart decompensation is provided,comprising an outer suppository shell having a melting pointapproximating normal body temperatures (about 3738 C.) containing acirculatory adjuvant such as camphor and an inner suppository corecontained Within and surrounded by the shell, the core having a meltingpoint a few degrees lower than normal body temperatures, preferablyabout 34-35 C., containing a cardiac glycoside, most preferably'strophanthin. I have surprisingly found that absorption of circulatoryadjuvants such as camphor in the rectum is much more rapid than throughmuscular tissue, and that such a plural medicament-containingsuppository having the indicated melting points can be compounded so asto successively liquefy the circulatory adjuvant and cardiac glycosideat those shorter intervals (of the order of a quarter hour) necessaryfor the production of the Interval Effect; While plural medicamentsuppositories have previously been described in the literature, I havefor the first time unexpectedly discovered that combination ofingredients which successfully produce a plural medicament suppositorycapable of sequential actuation of the various medicaments atspecifically timed intervals.

Preferably, the suppository of the invention possesses an outer shellincluding a frusto conical section and a conoidal section, the bases ofwhich are integral with one another. Such configuration of a pluralmedicamentcontaining suppository has been disclosed in the copendingapplication of Walther I. Bensegger and Johann H. Schaeppi, Serial No.524,983, filed July 28, 1955, now abandoned.

One embodiment of the suppository of this invention is shown in theattached drawing wherein the outer suppository shell 12 comprises acirculatory adjuvant dispersed in a liquefable carrier, and the innercore 11 contains a cardiac gly'coside dispersed in a relatively morereadily liquefiable carrier.

7 The method of formation of the suppository of this invention issimilar to that disclosed in the aforesaid copending application andcomprises pouring a liquid coating mass for the suppository shellcontaining a circulatory adjuvant around a mold core, which core extendsoutwardly from a casting chamber in the form of a base sectioncomprising a conoid adjoining and integral with a frusto conical sectiontaper-ing toward the chamber mouth, cooling to solidify the shell,removing the mold core from the mold and then pouring and solidifyingwithin the hardened shell a liquid coating mass for the suppository corecontaining a cardiac glycoside.

Upon insertion of the suppository of this invention into body orifices,the outer suppository shell containing the circulatory adjuvant firstliquefies and is absorbed into the blood stream. The suppository shell,which melts at about body temperature (3738 C.) permits the totalassimilation of the adjuvant such as camphor within ten snaaarstofifteen minutes" of administration of the suppository. Within theminute period the adjuvant acts upon the circulatory system to effectincrease of the blood supply to the right atrium of the heart. Thecarrier for the cardiac glycoside in the suppository core, on the otherhand, is so compounded as'to melt at a lower temperature than the shell,at about 3435 'C., so as to achieve much more rapid liquefaction andactuation of the active glycoside in the blood stream. The shell carrieris a fat-like substance which serves to insulate'the core material evenafter liquefaction of the shelland, in order to provide rapid actuationof the glycoside, a lower melting core material is utilized. It has beenfound that the cardiac glycoside will achieve its positive inotropiceffect Within five to ten minutes of complete liquefaction of thesuppository shell, i.e., within fifteen to twenty-five minutes ofadministration of the suppository of this invention.

The suppository core contains a cardiac glycoside dispersed in asuitable carrier, which carrier can be any of those well known in theart, such. as cocoa-butter (oil of theobroma), solidified glycerin, lardor a paraffinic wax. The composition of the core is so controlled thatthe melting point of the core is between about 34 and 35 C. Anemulsifying 'agent is included in the core composition to insure thehomogeneous dispersion of the cardiac glycoside upon liquefaction of thefat-like carrier materials. Emulsifying agents of the non-ionic type,such as derivatives of sorbitol, polyglycol ethers and the like, may beemployed as the emulsifying agents in question.

While any of the cardiac glycosides, such as strophanthin, digitalis,digitoxiin, scilloren A, krataegus, bufalin, or the like, may beemployed in the suppository composition, as may glycoside derivativessuch as the active aglycones (e.g. strophanthidin and periplogenin),experimental tests indicate that by far the most effective glycoside forthe practice of this invent-ion is strophanthin.

The strophanthin is contained within the suppository core in arnounts offrom 0.03% to 0.15% by weight, based on the weight of the coremedicament carrier.

In general, the core will represent from about onefifth to one-third ofthe total weight of the suppository, the shell the remaining four-fifthsto two-thirds. By the use of these weight ratios along with the choiceof carrier needed, the desired Interval Efiect is achieved.

The suppository shell contains a circulatory adjuvant dispersed in amedicament carrier, which latter may be cocoa-butter, solidifiedglycerin, lard or a parafiinic wax. The amounts of the carrier andadjuvant are adjusted so that the shell melts at about body temperature,VtiZ. 37- 38" C. in this fashion absorption of the adjuvant, such ascamphor, takes places in ten to fifteen minutes after rectaladministration. Camphor is the preferred adjuvant since it is absorbedinto the blood stream relatively rapidly 'by rectal suppositoryadministration and produces the least blood pressure increase whilesimultaneously promoting the motivity of the diagram. However, otheradjuvants such as hydroxy camphor, trans-r-oxocamphor,1-(3-hydroxyph'enyl) 1 hydroxy-Z-ethylaminethanol, 8- nicotinic aciddiethylarnide, or other sympathomimetics or circulatory analeptics canless preferably be used.

The circulatory adjuvant such as camphor, is employed in the suppositoryshell in amounts ranging from about 9% to 15% by weight, based on theweight of the shell medicament carrier. The adjuvant may be employed atthe lower percentage for amounts of the cardiac glycoside up to about0.075% of the weight of the carrier for the glycoside, but as the amountof the glycoside is increased above that value, it is preferred toincrease the amount of the adjuvant to a maximum of about 15% by weightof its carrier.

Example A suppository composition of the present invention was preparedaccording to the method and with the apwas added and, after agitation,the mixture was poured.

into a casting chamber as described in the above mentioned application.After cooling and solidification thereof, the mold core was removed fromthe casting chamber leaving the hardened suppository shell therein.

After formation of the suppository shell, a mixture of Estarinum B, withparaffin wax (melting point 50-52? C.)

and an emulsifying agent was heated and liquefied. To-

the liquid melt strophanthin was added and, after agitation, the mixturewas poured within the solidified suppository shell and allowed to hardento form the suppository core. The emulsifying agent employed wasAbsorbticnshasis 90, a product of Th. Muhlethaler S.A.,

Nyon, Switzerland, which emulsifier comprises a mixture. of saturatedhigh fatty alcohols and non-ionic surface active agents, derived fromS'orbitol; the emulsifying agent had a melting point of 34 C., a pH of 7and absorbed nine times its volume of water.

The finished suppository was found to Weigh 2.7 grams, of which 2 gramscomprised the outer shell. The suppository shell, which melted at 3738C., contained the.

following weight percentages of constituents:

Percent:

Estarinum l3 77" Paraflin wax 13'.5' Camphor 9.5

The core of the suppository, which melted at 34-35" C., contained byweight percentages, the following:

Percentv Estarinum B (carrier) 88.964 Paraffin wax 5.5 Absorbtionsbasis(emulsifying agent) 5.5 Strophanthin 0.036.

Upon rectal administration, the outer suppository shell was found tocompletely liquefy in fifteen minutes and the suppository core, whichmelted at a lower tempera-' ture, was totally liquefied within fiveminutes thereafter.

The above example is intended to be illustrative, and

not limiting, of a novel suppository prepared according to the presentinvention for achieving the synergistic therapeutic effect resultingfrom the successive administration at timed intervals of a circulatoryadjuvant and a cardiac glycoside.

Since difierent embodiments of the invention may be.

made without departing from the scope thereof, it is intended that allmatter contained in the above description shall be interpreted asillustrative and not in a limiting sense.

What is claimed is:

1. A plural medicament-containing layered suppositoryfor the treatmentof heart decompensation comprising,

in combination, an outer shell having. a melting point of 37-38 C. andcontaining, a circulatory adjuvant, and'an; inner core contained withinand surrounded bysaid shell having a melting point of 34-35 C. andcontainingv a cardiac glycoside.

2. A suppository as defined in claim 1 whereinsaidshell contains amedicament carrierand a circulatory adjuvant, saidadjuvant included inan amount of from about 9% to 15% by weight of said carrier, and saidcore contains a medicament carrier and acardiac glycoside,.

said glycoside included in an amount of from 0.103% to.

0.15% by weight of said last mentioned carrier.

3. A suppository as defined in claim 2 wherein said circulatory adjuvantcomprises camphor and. said cardiac glycoside comprises strophanthin.

4. A suppository as defined in claim 1 wherein said shell containscamphor as said adjuvant, said camphor being assimilable within thecirculatory system of the patient Within about to minutes of theadministration of said suppository, and said core contains strophanthinas said glycoside, said strophanthin being absorbed by said circulatorysystem subsequent to the absorption of said camphor and within 15 tominutes of the administration of said suppository.

5. A plural medicament-containing layered suppository for the treatmentof heart decompensation comprising, in combination, an outer shellhaving a melting point of 37-38 C. and containing a circulatoryadjuvant, said shell including a frusto conical section and a conoidalsection, the bases of said sections being integral with one another, andan inner core enclosed within said shell having a melting point of 3435C., said core containing a cardiac glycoside.

6. A suppository as defined in claim 5 wherein said shell contains amedicament carrier and a circulatory adjuvant, said adjuvant included inan amount of from about 9% to 15% by Weight of said carrier, and saidcore contains a medicament carrier and a cardiac glycoside, saidglycoside included in an amount of from 0.3% to 0.15% by Weight of saidlast mentioned carrier.

7. A suppository as defined in claim 6 wherein said circulatory adjuvantcomprises camphor and said cardiac glycoside comprises strophanthin.

8. A suppository as defined in claim 5 wherein said shell containscamphor as said adjuvant, said camphor being assimilable within thecirculatory system of the patient within about 10 to 15 minutes of theadministration of said suppository, and said core contains strophanthinas said glycoside, said strophanthin being absorbed by said circulatorysystem subsequent to the absorption of said camphor and within 15 to 25minutes of the administration of said suppository.

References Cited in the file of this patent UNITED STATES PATENTS OTHERREFERENCES Brodhage et al.: Arzneimittel-forchung, vol. 7, (1957), pp.387-388.

Lendle et al.: Arch. fiir Experimentalle Pathologie und Pharmakolocie,vol. 138, (1938), pp. 317-327.

U.S. Dispensatory, 25th ed., Lippincott Co., Philadelphia, Pa., (1955),p. 232-4.

Sollman: Manual of Pharmacology, 8th ed., Saunders Co., Philadelphia,Pa. (1957), pp. 249-251.

Ser. No. 143,736, Hatfner (A.P.C.), published May 11, 1943.

1. A PLURAL MEDICAMENT-CONTAINING LAYERED SUPPOSITORY FOR THE TREATMENTOF HEART DECOMPENSATION COMPRISING, IN COMBINATION, AN OUTER SHELLHAVING A MELTING POINT OF 37-38* C. AND CONTAINING A CIRCULATORYADJUVANT, AND AN INNER CORE CONTAINED WITHIN AND SURROUNED BY SAID SHELLHAVING A MELTING POINT OF 34-35*C. AND CONTAINING A CARDIAC GLYCOSIDE.